ABSTRACT Diabetes affects more than 387 million individuals worldwide. In the U.S., a condition that precedes type 2 diabetes, prediabetes, impacts 37-38% of Americans. Of these individuals, 15 million Americans have diabetic neuropathy (DN), a debilitating microvascular complication that results in the progressive loss of sensory nerve function in the extremities. Despite the deleterious impact of DN, therapies for the disease are limited to symptomatic relief. To develop effective treatments that specifically target DN, a mechanistic understanding of molecular pathways that result in neurological dysfunction associated with prediabetes is needed. Recent evidence suggests that dyslipidemia, rather than hyperglycemia, is the clinical parameter that correlates with the progression of DN. Since metabolic pathways converge on mitochondria (Mt), these organelles play a central role in maintaining neuronal cellular function and energy homeostasis through mitochondrial (Mtl) trafficking mechanisms and endoplasmic reticulum (ER)-mediated calcium signaling pathways. However, metabolic overload associated with prediabetes may result in aberrant calcium dynamics in the primary sensory neurons of the nervous system, the dorsal root ganglia (DRG), resulting in diminished Mtl trafficking and cell death induced by ER-Mt contact sites. We hypothesize that hyperlipidemia increases the level of ER- Mt contact in DRG neurons, creating localized calcium flux which triggers Mtl apoptosis and halts Mtl trafficking by inducing conformational changes in motor proteins. We will test this hypothesis by 1) evaluating the role of ER-Mt interactions in Mtl dysfunction and neuronal cell death in the DRG and sural nerve of a high fat (HF)-fed mouse model, and 2) identifying structural and functional changes in Mtl motor/adaptor protein complexes that impair Mtl trafficking in hyperlipidemic DRG neurons. These studies will provide important insight into the role of Mtl dynamics in DN and support our long-term goal of identifying therapeutic targets that improve Mtl function and restore nerve function to patients with DN.